DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation.

DNA is constantly exposed to endogenous and exogenous mutagenic stimuli that are capable of producing diverse lesions. In order to protect the integrity of the genetic material, a wide array of DNA repair systems that can target each specific lesion has evolved. Despite the availability of several repair pathways, a common general program known as the DNA damage response (DDR) is stimulated to promote lesion detection, signaling, and repair in order to maintain genetic integrity. The genes that participate in these pathways are subject to mutation; a loss in their function would result in impaired DNA repair and genomic instability. When the DDR is constitutionally altered, every cell of the organism, starting from development, will show DNA damage and subsequent genomic instability. The cellular response to this is either uncontrolled proliferation and cell cycle deregulation that ensues overgrowth, or apoptosis and senescence that result in tissue hypoplasia. These diverging growth abnormalities can clinically translate as cancer or growth retardation; both features can be found in chromosome instability syndromes (CIS). The analysis of the clinical, cellular, and molecular phenotypes of CIS with intrauterine growth retardation allows inferring that replication alteration is their unifying feature.

[Non invasive prenatal test (NIPT) in maternal blood by parallel massive sequencing. Initial experience in Mexican women and literature review]. / Prueba prenatal no invasiva (NIPT) en sangre materna a través de secuenciación masiva paralela (MPS). Experiencia inicial en mujeres mexicanas y revisión de la bibliografía.

BACKGROUND: Discovery of cell-free fetal DNA (cffDNA) in maternal blood in 1997 by Lo et al. has opened the possibility of a noninvasive prenatal test (NIPT). Currently, it is employed in the analysis of aneuploidies and fetal sex determination. Massive parallel sequencing (MPS) detects the origin of each amplified sequence, and analyses over-representation of sequences or any decrease in the fetal chromosomes in maternal plasma. This technique has been validated and allows assessment of trisomies 13, 18 and 21, obtaining the result in about a week from 10-weeks of gestational age. By using NIPT, we expect a reduction in the number of invasive studies and the risk of fetal loss. OBJECTIVE: To communicate the experience obtained at Genetics Clinic of the Hospital Angeles Lomas, in the use of NIPT by MPS as a method of prenatal screening for aneuploidies and fetal sex determination. MATERIAL AND METHODS: A prospective, observational and descriptive study was carried out in order to develop a database of patients who underwent NIPT (Harmony test) from August 2013 to date. Maternal blood samples were analyzed at Ariosa Diagnostics Inc. at San Jose California, USA. RESULTS: Noninvasive prenatal test was applied to 42 patients, with average maternal age of 37.1 years. The percentage of gestational age was 13.3 weeks and of fetal fraction was 12.7%. Two cases of high risk of trisomy 18 and two cases with high risk for X monosomy were obtained. In only one case the test was used for fetal determination, because of a story of Wiskott-Aldrich (W-A) disease. In all cases of low risk, the result was confirmed at birth and fetal sex was consistent with reports of literature. CONCLUSIONS: NIPT is currently the screening test with the highest detection rate (greater than 98%, with a false negative rate lesser than 0.5% and a sensitivity and specificity close to 100%), although it can vary from one chromosome to another. It is indicated for women with a result of high risk for trisomy 13, 18 and 21. This test has not been validated for low risk women or multiple pregnancies. In our series, the most frequent indication was advanced maternal age. The weight of the patients is important because it is a factor related to the percentage of fetal DNA. In cases with high risk for X monosomy in which the cytogenetic result was 46, XX, it is important to consider as much causes as possible, such as uniparental disomy (UPD), mosaicism and maternal contamination. Only in a case with W-A story the test was conducted specifically for fetal sex determination and confirmed by amniocentesis. In the cases of high-risk results, confirmation by an invasive method, before an obstetric decision, is indispensable. Further studies are still needed to continue the validation of this test by different molecular techniques and in other groups of patients.

[Recurrent aneuploidy in first trimester gestational loss: a case report and review of the literature]. / Aneuploidía recurrente en pérdida gestacional del primer trimestre: reporte de un caso y revisión de la bibliografía.

Miscarriage is the loss of pregnancy before 20 weeks of gestation and occurs in 15% of clinically recognized pregnancies. However, 5% of couples present recurrent abortion, which means more than two losses whether consecutive or not. One of the main causes of both, spontaneous and recurrent abortion, are genetic. Within it, chromosomal abnormalities are the most important. So far, the only risk factor that has been clearly defined is maternal age. Nevertheless, in patients with recurrent abortion, there has been research on some other factors that generate a greater predisposition to aneuploidy, and consequently, recurrent abortion risk. One of the mechanisms that may be the link between aneuploidy risk and maternal age is the level of Follicle Stimulating Hormone (FSH). This is due to the fact that elevated levels of Follicle Stimulating Hormone have been found to modify the morphology of meiotic spindles, which in turn leads to a higher risk of aneuploidy. In this article we present a literature review on the subject, as well as the case of a patient with two abortions, one of them with trisomy 13, and the other with trisomy 18.

[Birth defects associated with increased nuchal translucency]. / Defectos congénitos asociados con translucencia nucal aumentada.

BACKGROUND: Nuchal translucency is widely used to screen for trisomy 21 in the first trimester of pregnancy. It has also been associated with other chromosomal abnormalities, genetic syndromes and congenital defects. OBJECTIVE: To evaluate the perinatal outcome of patients who showed nuchal translucency greater or equal to 95th percentile during the first trimester ultrasound screening, which underwent fetal karyotype. MATERIAL AND METHOD: Case series. Fetuses with nuchal translucency greater or equal to 95th percentile were evaluated by fetal karyotype, second-trimester structural ultrasound scan, fetal echocardiography and postnatal clinical genetic evaluation, attended in the servicio de Genética of the Instituto Nacional de Perinatología Isidro Espinosa de los Reyes. RESULTS: 48 fetuses were evaluated. The karyotype was normal in 39 (81%) and abnormal in 9 (19%) cases of which three had trisomy 21, three monosomy X, two trisomy 18 and one 47,XYY In the cases with normal karyotype, 13 (33%) showed an abnormal second trimester ultrasound scan; among them, 12 had major congenital defects, 5 of them had abnormal cardiac findings that were confirmed by fetal echocardiography. In the group of 26 fetuses with normal karyotype and ultrasound, only 2 patients had minor birth defects. CONCLUSIONS: Increased fetal nuchal translucency is frequently associated with chromosomal abnormalities and several congenital defects, mostly heart defects and genetic syndromes. Our findings are in accordance with other published reports where a complete follow-up of all patients with increased nuchal translucency is recommended even if they have a normal karyotype, due to the increased risk of having other congenital defects or syndromic entities.